Proteome-wide Analysis and CXCL4 as a Biomarker in Systemic Sclerosis

被引：350

作者：

van Bon, L. ^{[1
,3
,4
]}

Affandi, A. J. ^{[1
,3
,4
]}

Broen, J. ^{[1
,3
,4
]}

Christmann, R. B. ^{[1
]}

Marijnissen, R. J. ^{[3
,4
]}

Stawski, L. ^{[1
]}

Farina, G. A. ^{[1
]}

Stifano, G. ^{[1
]}

Mathes, A. L. ^{[1
]}

Cossu, M. ^{[3
,4
,12
]}

York, M. ^{[1
]}

Collins, C. ^{[1
]}

Wenink, M. ^{[3
,4
]}

Huijbens, R. ^{[3
,4
]}

Hesselstrand, R. ^{[14
]}

Saxne, T. ^{[14
]}

DiMarzio, M. ^{[1
]}

Wuttge, D. ^{[14
]}

Agarwal, S. K. ^{[15
]}

Reveille, J. D. ^{[15
]}

Assassi, S. ^{[15
]}

Mayes, M. ^{[15
]}

Deng, Y. ^{[2
]}

Drenth, J. P. H. ^{[6
]}

de Graaf, J. ^{[7
]}

den Heijer, M. ^{[8
]}

Kallenberg, C. G. M. ^{[11
]}

Bijl, M. ^{[11
]}

Loof, A. ^{[9
]}

van den Berg, W. B. ^{[3
,4
]}

Joosten, L. A. B. ^{[7
]}

Smith, V. ^{[16
]}

de Keyser, F. ^{[16
]}

Scorza, R. ^{[12
]}

Lunardi, C. ^{[13
]}

van Riel, P. L. C. M. ^{[10
]}

Vonk, M. ^{[10
]}

van Heerde, W. ^{[9
]}

Meller, S. ^{[17
]}

Homey, B. ^{[17
]}

Beretta, L. ^{[12
]}

Roest, M. ^{[5
]}

Trojanowska, M. ^{[1
]}

Lafyatis, R. ^{[1
]}

Radstake, T. R. D. J. ^{[1
,3
,4
]}

机构：

[1] Boston Univ Sch, Arthrit Ctr, Boston, MA USA

[2] Boston Univ Sch, Flow Cytometry Core Facil, Boston, MA USA

[3] Univ Med Ctr Utrecht, Dept Rheumatol & Clin Rheumatol, Utrecht, Netherlands

[4] Univ Med Ctr Utrecht, Lab Translat Immunol, Utrecht, Netherlands

[5] Univ Med Ctr Utrecht, Dept Clin Chem & Hematol, Res Lab, Utrecht, Netherlands

[6] Radboud Univ Nijmegen, Med Ctr, Dept Gastroenterol & Hepatol, NL-6525 ED Nijmegen, Netherlands

[7] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 ED Nijmegen, Netherlands

[8] Radboud Univ Nijmegen, Med Ctr, Dept Endocrinol, NL-6525 ED Nijmegen, Netherlands

[9] Radboud Univ Nijmegen, Med Ctr, Cent Hematol Lab, NL-6525 ED Nijmegen, Netherlands

[10] Univ Med Ctr Nijmegen, Dept Rheumatol, Nijmegen, Netherlands

[11] Univ Groningen, Univ Med Ctr Groningen, Dept Rheumatol & Clin Immunol, Groningen, Netherlands

[12] Fdn IRCCS Ca Granda Osped Maggiore Policlin Milan, Referral Ctr System Autoimmune Dis, Milan, Italy

[13] Univ Verona, I-37100 Verona, Italy

[14] Univ Lund Hosp, Dept Rheumatol, S-22185 Lund, Sweden

[15] Univ Texas Hlth Sci Ctr Houston, Div Rheumatol, Dept Internal Med, Houston, TX 77030 USA

[16] Ghent Univ Hosp, Ghent, Belgium

[17] Univ Dusseldorf, Dept Dermatol, Dusseldorf, Germany

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2014年 / 370卷 / 05期

基金：

欧洲研究理事会;

关键词：

LUPUS-ERYTHEMATOSUS; REVISED CRITERIA; SCLERODERMA SKIN; I INTERFERONS; DISEASE; CELLS; PLATELET-FACTOR-4; CLASSIFICATION; ASSOCIATION; ACTIVATION;

D O I：

10.1056/NEJMoa1114576

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BackgroundPlasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon. MethodsWe isolated plasmacytoid dendritic cells from healthy persons and from patients with systemic sclerosis who had distinct clinical phenotypes. We then performed proteome-wide analysis and validated these observations in five large cohorts of patients with systemic sclerosis. Next, we compared the results with those in patients with systemic lupus erythematosus, ankylosing spondylitis, and hepatic fibrosis. We correlated plasma levels of CXCL4 protein with features of systemic sclerosis and studied the direct effects of CXCL4 in vitro and in vivo. ResultsProteome-wide analysis and validation showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in circulation and in skin. The mean (SD) level of CXCL4 in patients with systemic sclerosis was 25,6242652 pg per milliliter, which was significantly higher than the level in controls (92.577.9 pg per milliliter) and than the level in patients with systemic lupus erythematosus (1346 +/- 1011 pg per milliliter), ankylosing spondylitis (1368 +/- 1162 pg per milliliter), or liver fibrosis (1668 +/- 1263 pg per milliliter). CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro, CXCL4 down-regulated expression of transcription factor FLI1, induced markers of endothelial-cell activation, and potentiated responses of toll-like receptors. In vivo, CXCL4 induced the influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis. ConclusionsLevels of CXCL4 were elevated in patients with systemic sclerosis and correlated with the presence and progression of complications, such as lung fibrosis and pulmonary arterial hypertension. (Funded by the Dutch Arthritis Association and others.)

引用

页码：433 / 443

页数：11

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